Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.
Bovine Respiratory disease complex (BRDC) is the most significant infectious disease of feedlot cattle in Australia. BRDC causes economic loss due to morbidity, mortality, loss of feed resources, medication purchases, increased time on feed and associated labor costs. BRDC has a complicated etiology with at least four viral and three bacterial species along with environmental conditions predisposing an animal to the illness.
The four viruses associated with BRDC are bovine herpesvirus 1 (BoHV-1), bovine viral diarrhea virus (BVDV or bovine pestivirus), bovine parainfluenza 3 virus and bovine respiratory syncytial virus. Serological surveys have shown that all of these viruses infect feedlot cattle in Australia. Three bacterial species, Pasteurella mutocida, Manhiemia haemolytica and Haemophilus somnus, have also been implicated in BRDC.
In North America and in Europe, both live and killed vaccines have been used to control diseases caused by BoHV-1. These vaccines are based on different genotypes of BoHV-1 to that found in Australia. North American and European BoHV-1 strains are generally classified into the subgroup 1.1 while Australian strains form the subgroup 1.2. The BoHV-1.1 viruses cause a more severe clinical disease compared to the BoHV-1.2 viruses. The exact molecular mechanism for this difference in phenotype is unknown.
BoHV-1 is a virus of the family Herpesviridae that causes several diseases worldwide in cattle, including rhinotracheitis, vaginitis, balanoposthitis, abortion, conjunctivitis and enteritis. BoHV-1 is also a contributing factor in shipping fever. It is spread through sexual contact, artificial insemination and aerosol transmission. Like other herpesviruses, BoHV-1 causes a lifelong latent infection and shedding of the virus. The sciatic nerve and trigeminal nerve are the sites of latency.
The respiratory disease caused by BoHV-1 is commonly known as infectious bovine rhibotracheitis. Symptoms include fever, discharge from the nose, cough, difficulty in breathing and loss of appetite. Ulcers commonly occur in the mouth and nose. Mortality rates may reach 10 percent. The genital disease causes infectious pustular vulvovaginitis in cows and infectious balanoposthitis in bulls. Symptoms include fever, depression, loss of appetite, painful urination, a swollen vulva with pustules and discharge in cows and pain on sexual contact in bulls. In both cases, lesions usually resolve within two weeks. Abortion and stillbirths can occur one to three months post infection. BoHV-1 also causes a generalized disease in newborn calves, characterized by enteritis and death.
Similarly, BVDV is a disease of cattle which reduces productivity and increases mortality. It is caused by a pestivirus from the family Flaviviridae. Pestiviruses have the ability to establish persistent infection during pregnancy. Persistent infection with pestiviruses often goes unnoticed. BVDV also frequently undergoes non-homologous RNA recombination leading to the appearance of genetically distinct viruses that are lethal to the host.
Clinical signs of mucosal erosions and diarrhea which occur in the acute form of bovine viral diarrhea have a significant effect on those animals infected, but much more costly are animals which are persistently infected. Typically, such animals fail to reach their genetic potential, exhibiting decreased weight gain, increased disease susceptibility and reduced fertility. They shed the virus causing reproductive loss in the unimmunized animals in the herd.
Cows that are exposed to the cytopathic variant of BVDV (45-125 days gestation) will typically abort the fetus. Earlier exposure to either variant leads to early embryonic death. Exposure between days 125-175 days of gestation leads to birth defects (such as ocular defects and hydrocephalus) and exposure at greater than 175 days will typically lead to the calf being fully immune at birth.
Therefore, as a consequence of the severity of BRDC and the significant effect on the livestock industry improvements in vaccination are required. Attenuated viruses give better protection than inactivated viruses because they present more viral antigens to the immune system of the host. Another important advantage of the attenuated virus is the potential to administer it intranasally, i.e. at the site where the first multiplication of the wild-type virus occurs after infection.
It has long been recognized that the antigenic variability of BVDV makes it a difficult virus against which to vaccinate. There are two approaches which can be taken for BVDV specific vaccination. One is the induction of neutralizing antibodies which prevent the target virus from infecting cells. The second is the induction of cell-mediated immunity (CMI) which targets virus infected cells for destruction, thus reducing the effects of a viral infection. The major neutralizing epitopes of BVDV are the structural glycoproteins and as a result of immune selection, these proteins are also the most variable. Thus, designing a vaccine based on the glycoproteins requires the inclusion of the most common antigenic types. The non-structural proteins of BVDV are generally more conserved as they have a specific enzyme function which limits the variation in the protein sequences that can occur.
For a proper BRDC control program, it is necessary to have an efficacious and safe vaccine that can be distinguished from the wild-type virus. Previously developed vaccines using BoHV-1 were constructed with deletions to glycoproteins and/or comprised a thymidine kinase deletion mutant. There have been problems with these vaccines as the thymidine kinase gene is involved in viral replication and less replication can lead to less protection due to lower levels of glycoproteins which are involved in the generation of humoral immunity.
There is a need to develop improved and more efficacious vaccines which enable control of BRDC and particular pathogens associated therewith.